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Biomedical subjects

R R Young

Publications and source records attributed to R R Young.

At least 19 recordsLinked to original sources

Genetic toxicology evaluation of commercial beers, III. SCE, chromosome aberrations, and forward mutation (HGPRT) of commercial beer products in CHO cells.

Concentrated organic residues extracted from 5 blended aliquots of commercial beers were evaluated for their ability to induce sister chromatid exchange (SCE), chromosomal aberrations and forward mutation in Chinese hamster ovary (CHO) cells. Each extract was prepared by blending 4 commercial beers of similar ingredients and brewing method, passing the beer pool over XAD-2 resin, extracting the resin and concentrating the extract. Studies were performed both with and without metabolic activation using variable amounts of reconstituted residues from 225-fold concentrates of the blended samples. CHO cultures were treated with 0.75 microliters/ml through 10.0 microliters/ml of the concentrates in the SCE assays, 1.0 microliters/ml through 10.0 microliters/ml of the extracts in the aberration assays and 2.5 microliters/ml up to 20 microliters/ml for forward mutation assays. In preliminary screening for SCE as an indicator of potential DNA damage, a significant increase was observed for 3 of 5 concentrated samples; however, no increase in SCE was induced by any of the 5 samples when S9 was added as a source of exogenous metabolic activation. More definitive tests for induction of genetic events, i.e., chromosome aberrations and forward HGPRT mutations, were negative for all 5 extracts whether or not S9 mix was present. Since SCE were not induced in tests with metabolic activation and since there was no concordant aberration or point mutation induction, the preliminary indication of potential DNA damage shown by elevated SCE under conditions without metabolic activation appears to have little biological significance.

Animals

Assessment of the potential genotoxicity of perfluorodecanoic acid and chlorotrifluoroethylene trimer and tetramer acids.

Perfluoro-n-decanoic acid (PFDA) is a perfluorinated fatty acid that produces hepatomegaly and increased peroxisomal beta-oxidation when administered to rodents. Chlorotrifluoroethylene (CTFE) trimer acid and CTFE tetramer acid are metabolites of the six- and eight-carbon oligomers of CTFE, respectively. They are structurally related to PFDA, and CTFE tetramer acid has caused toxic effects in rodents that are similar to those observed following PFDA administration. Because of the correlation between peroxisome proliferation and hepatocarcinogenesis, CTFE trimer acid, CTFE tetramer acid, and PFDA were evaluated in in vitro and in vivo/in vitro bioassays to assess their potential genotoxic activity. The assays conducted were the Ames Salmonella/microsomal mutagenicity assay, the hypoxanthineguanine phosphoribosyltransferase (HGPRT) locus Chinese hamster ovary gene mutation assay, the sister chromatid exchange (SCE) assay, chromosomal aberration assay, and an in vivo/in vitro unscheduled DNA synthesis (UDS) and S-phase DNA synthesis assay. All test articles were negative in the Ames assay, the HGPRT assay, and the SCE assay. In the chromosomal aberration assay CTFE trimer acid and CTFE tetramer acid were negative in cultures with and without S9 metabolic activation. PFDA was also negative in the absence of metabolic activation, but chromosomal aberrations were observed when PFDA was incubated in the presence of S9 fraction. All test articles were negative for inducing UDS but all induced S-phase replicative DNA synthesis 16 hr after administration of the test article to the test animals; only CTFE tetramer acid and PFDA induced S-phase synthesis 48 hr after dosing: the usual timepoint examined for this response.

Animals

Headaches in patients with traumatic lesions of the cervical spinal cord.

We established the occurrence of headache in a group of 20 patients with traumatic transections of the cervical spinal cord. All but two patients had complete sensory lesions at levels varying from C2-3 to C7-8. Only three patients claimed to have no headaches at all although one of them had nuchal pains with fever. Twelve patients had "bladder" or "bowel headaches" or had had them in the past. These headaches were mostly generalized, throbbing or pounding in nature and severe in intensity. They were caused by obstruction of urinary flow and fecal impaction, respectively, and were associated with autonomic dysreflexia. Otherwise the headaches reported by the patients were mild although frequent in four, i.e once per week or more. These headaches were also mostly bilateral and lasted a relatively short time, i.e. less than one or two hours. The causes of these headaches were nonspecific for the group studied except for stimulation of the body which, however, probably depended on a mechanism similar to that of the bladder and bowel headaches. Migraine, either classic or common, was not reported by any of the patients.

Adult

Recurrent inhibition is increased in patients with spinal cord injury.

Mechanisms underlying the development of spasticity after spinal cord injury are not understood. One spinal interneuron likely to be affected is the Renshaw cell, which acts to produce recurrent inhibition in motor neurons as well as inhibiting Ia interneurons. Descending pathways exert both excitatory and inhibitory control over Renshaw cell activity. We studied Renshaw cell activity in normal subjects and in patients with varying levels of spasticity after spinal cord injury using the conditioned H-reflex technique of Pierrot-Deseilligny and Bussel. A submaximal stimulus to the tibial nerve is presented prior to a supramaximal stimulus so that action potential collision permits an H reflex (H') to be elicited in response to the supramaximal stimulus. The amplitude of this H' reflex is affected by activity in recurrent inhibitory pathways. Patients with both complete and partial spinal cord lesions were studied; date of injury ranged from 1 month to 216 months prior to evaluation. In the 18 patients in whom H reflexes could be recorded, H' reflexes were absent in 13, in contrast to their uniform presence in normal subjects. We conclude that recurrent inhibition via Renshaw cell activity is increased in spinal cord injury, and that measures of recurrent inhibition may correlate well with some clinical measures of spasticity.

Adult

Innervation zone of orbicularis oculi muscle and implications for botulinum A toxin therapy.

Motor points (areas of maximal sensitivity to electrical stimulation) were found in constant locations over orbicularis oculi when measured in both eyes of six normal subjects. All subjects had a motor point at the lateral terminus of the upper lid crease and the medial extent of the lower lid crease. A study of the innervation zone [distribution of neuromuscular junctions (NMJ)] was conducted on strips of pretarsal and preseptal portions of the upper eyelid orbicularis that had been removed routinely during involutional ptosis surgery. There was no significant difference in NMJ concentration between the medial and lateral sections, as determined by cholinesterase staining. Therefore, we concluded that the innervation zone is diffuse for the orbicularis muscle within this portion of the upper eyelid. Single-point injections of botulinum toxin were then compared to the conventional multiple injection sites on separate eyes in 10 patients with benign essential blepharospasm. Eight of the 10 patients reported greater relief on the side given injections into multiple points; the other two patients experienced no difference between the two methods. Both histologic data and clinical observation of response to botulinum toxin injection suggest the innervation zone for the upper orbicularis is diffuse. Thus, we conclude that multiple injections are superior to the injection of a single motor point.

Acetylcholinesterase

Abnormal most-rapid isometric contractions in patients with Parkinson's disease.

Fast isometric elbow flexor muscle contractions of specified amplitude in six normal subjects were compared with those of 11 patients with Parkinson's disease. Despite treatment, all patients exhibited deficits in this motor task. Three patients were able to produce rapid force pulses with normal contraction times, but the variability of their force responses was increased in comparison with the highly stereotyped responses produced by normal subjects. The other eight patients had prolonged contraction times and segmentation of the force profiles. The integrated area of the first agonist EMG burst and the rate of development of force (dF/dt) were less at any target level than what was needed to produce a fast response. The area of the EMG burst, however, did increase with target amplitude, and the relative increase of dF/dt, with target amplitude, was normal. It is concluded that the motor program subserving fast muscle contraction is preserved in Parkinson's disease, but its execution is characterised by improper scaling of motor output.

Adult

The clinical diagnosis of disorders of the spinal cord.

Disease of the spinal cord or cauda equina may cause pain, motor abnormalities, sensory disturbance, alteration of reflexes and muscle tone, and bladder dysfunction. These five neurologic abnormalities occur in various combinations, evolve rapidly or slowly, and result in one of eight possible spinal cord syndromes. When a particular syndrome is defined by neurologic history and examination, differential diagnosis is limited to only a few possible disorders. An appropriate neuroradiologic or electrophysiologic procedure done at this point will usually provide the correct diagnosis.

Humans

Motor unit synchronization in physiologic, enhanced physiologic, and voluntary tremor in man.

Synchronization between pairs of single motor units simultaneously recorded from wrist extensor muscles was quantitated in 3 normal subjects during physiologic tremor (PT), beta-adrenergically enhanced physiologic tremor (EPT), and fast voluntary wrist flexion-extension movements mimicking tremor (VT). Cross-correlation histograms generated from the two spike trains of each motor unit pair demonstrated central or paracentral peaks in 13/19 recordings during PT, 22/36 during EPT, and 6/7 during VT. Relative peak area was used as a quantitative index of synchronization between the two motor units of each pair. It was lowest in PT, progressively increased in EPT as tremor amplitude increased, and highest in VT. In PT and lower amplitude EPT, the synchronization indexes were higher between motor units that discharged at the same or nearly the same frequency. In contrast, in higher amplitude EPT and VT, motor units with different firing frequencies were sometimes strongly synchronized as a consequence of double discharges in faster-firing motor units that had burst repetition rates in the range of slower-firing motor units discharging as singlets. Greater motor unit synchronization with increasing tremor amplitude in EPT may be secondary to a simultaneous increase in muscle spindle afferent activity from the tremulous muscle. Greatest synchronization in VT presumably reflects near maximal supraspinal and segmental common synaptic input onto motoneurons that generate VT. These results support a longstanding hypothesis that synchronization of motor units is the physiological basis for higher amplitude tremor.

Electromyography

Brain stem auditory evoked responses: studies of waveform variations in 50 normal human subjects.

Brain stem auditory evoked responses (BAERs) were recorded in 50 normal adult subjects at various click rates. Attention was paid to absolute latencies, interwave latencies, interear interwave latencies, absolute amplitudes, and various amplitude ratios. The variability of waves VI and VII suggests that the clinical utility of these waves is restricted-their absence is not necessarily due to a CNS lesion. The wave IV-V complex appears with six different patterns. These variations must therefore be considered normal; none should be misconstrued as indicative of disease of the CNS. Repeated studies over a period of two to nine months showed no statistically significant changes in amplitude or latency measurements with the passage of time. Knowledge of these normal values and their variations, as a precondition for establishing criteria for abnormality, is essential to the interpretation of BAERs in clinical situations.

Acoustic Stimulation

The effect of metrizamide on the electroencephalogram: a prospective study in 61 patients.

A prospective study was made of changes in the electroencephalogram after the use of metrizamide for myelography and posterior fossa cisternography in 61 patients (62 studies). The EEG changed in 21 patients (34%); 3 of these had had previously abnormal records, and the abnormalities were accentuated on the second recording. Eight developed paroxysmal activity, including spike and wave in 1. EEG changes appeared 24 to 48 hours after the use of metrizamide in 6 patients whose intervening EEGs were normal. The percentage of records that changed tended to increase as metrizamide was brought to more rostral levels. Symptoms following the use of metrizamide were reviewed in 58 patients. Although there were no seizures in the present series, seizures did occur with subsequent use of metrizamide in 3 other patients at our institution. Previous reports may have underestimated the frequency of EEG changes after metrizamide since these may require 24 to 48 hours to develop. The appearance of such activity suggests that the use of metrizamide in patients with known seizure disorders, the anatomical level to which metrizamide is brought during radiography, removal of contrast medium, and further investigation of premedication with anticonvulsants all require careful consideration when use of metrizamide is being contemplated.

Adult

Participation of the stretch reflex in human physiological tremor.

Microneurographic studies were made of normal human muscle spindle afferent activity to evaluate the role played by these endings, and by the segmental stretch reflex, in various types of physiological tremor. Primary endings are sufficiently sensitive to respond to the minute tremulous movements normally seen in contracting muscles. Human muscle spindle endings appear to possess the same non-linear sensitivity to small stretches as has been reported for cat muscle spindles. The findings also support the notion that the segmental stretch reflex plays an important role in enhanced physiological tremor, in so far as it tends to synchronize the motor outflow in such a way as to produce rhythmical contractions properly timed to reinforce the mechanical resonant properties of muscle spindle endings, the stretch reflex also serves to damp the larger oscillations of finger or hand which result from a brisk tap or muscle twitch. There is no evidence for alpha-gamma co-activation in these enhanced physiological tremors.

Afferent Pathways

Assessing segmental excitability after acute rostral lesions: II. The blink reflex.

Blink reflexes were obtained in a total of 34 different patients with cerebrovascular lesions; 28 were studied within 1 week of the ictus and 11 were eventually restudied. In 13, the latency of the first component of the reflex on the clinically involved side was significantly delayed (greater than 1.5 msec). This was an acute phenomenon that usually resolved within the first week after the ictus, correlated clinically with the severity of the hemiparesis and decrease in tone, and may be seen with lesions restricted to the pyramidal tract. The second component was absent in 17 of 34 patients during the early phase after stroke, and was associated with a decreased corneal response. These changes, which reflect decreased excitability of certain brainstem structures (rather than a lesion within those structures), are therefore potentially important for documenting CNS pathophysiology.

Cerebrovascular Disorders

The importance of studying sural nerve conduction and late responses in the evaluation of alcoholic subjects.

Motor conduction velocities of median, ulnar, peroneal, and tibial nerves and sensory conduction velocities of median and ulnar nerves were studied in 30 alcoholic subjects and a similar group of control subjects. The results were compared to sural nerve conduction velocities and late response latencies (H reflex, F response). The latter two techniques improved the diagnostic yield by 20%: Whereas 73% of our patients showed an abnormality of conduction with conventional techniques, 93% had an abnormality of sural nerve conduction, late response latencies, or both. Abnormalities of motor and sensory conduction, which were more prominent in the lower limbs than the arms, could be documented in patients who did not have any clinical evidence of peripheral neuropathy. The electrophysiologic studies performed in the present study suggest that "axonal degeneration" is the underlying pathologic process in alcoholic peripheral nerve disease.

Adult

Impact of CT on EEG.

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Electroencephalography